Nanophthalmos is a heritable condition characterized by a small, but structurally normal eye, with resultant high hyperopia (+8D to +25D). Defining features of nanophthalmos include a short axial length (less than 20-21 mm), with a proportional decrease in anterior segment dimensions, i.e., corneal diameter and anterior chamber depth. Despite a reduction in global ocular volume, the eye contains a normal sized lens.
Nanophthalmos is usually a sporadic disorder. Six major genes have been implicated in isolated nanophthalmos, including MFRP, PRSS56, BEST1, TMEM98, CRB1, and MYRF . For two of these genes (TMEM98, MYRF), the trait is inherited in an autosomal dominant manner, while the remaining genes cause recessive disease (MFRP, PRSS56, BEST1, CRB1). Additionally, several genes have been associated with nanophthalmos as part of a multisystem syndrome, including MYRF and FAM111A.
Nanophthalmos may present as an isolated disorder or be part of a syndrome. These syndromes include: “nanophthalmos, retinitis pigmentosa, foveoschisis and optic drusen syndrome”, “oculo-dento-digital syndrome (ODD syndrome)”, “autosomal dominant vitreoretinochoroidopathy with nanophthalmos (ADVIRC)”and “Kenny-Caffey syndrome”.
Defining the genetic etiology is important for patient counseling and management since the different genetic causes are associated with varying ocular and systemic features. Glaucoma and other ocular complications secondary to nanophthalmos may be difficult to manage and genetic diagnosis can be helpful for early recognition.
Nanophthalmos is frequently associated with ocular complications, presenting as high hyperopia with amblyopia and partially accommodative esotropia in early childhood. Given the anterior segment structure, patients are predisposed to angle closure and the resulting angle closure glaucoma, and often need cataract surgery early in life. Many cases of nanophthalmos complicate with uveal effusion with or without exudative retinal detachment. This is attributed to blockage of outflow from the vortex venous system secondary to a thickened sclera.
On distant direct ophthalmoscopic examination or indirect ophthalmoscopy without using a lens, a peculiar glow can be seen and the retinal vessels may be visible. Prominent iris convexity and impending angle closure with peripheral anterior synechiae (that may eventually form) may be observed beyond the fourth decade.
Diagnosis and monitoring for glaucoma in nanophthalmos are rather difficult due to a small disc, where even a small cup may be a sign of glaucoma. Additionally, visual field testing can be inaccurate because many patients have high plus lenses and reduced BCVA. In these cases SD OCT may detect subtle wedge-shaped loss of nerve fiber layer. HRT may assist in monitoring the deterioration of disc parameters. Stereo fundus photos can offer reliable documentation of disc morphology. These patients are also predisposed to malignant glaucoma.
Histology shows all three scleral layers have abnormal collagen fibrils that are frayed and split. The frayed fibrils contribute to scleral inelasticity which causes sequestration of extracellular fluid and consequently choroidal congestion, choroidal detachment, and/or exudative retinal detachment.
Vision loss may also result from other associated retinal findings, including foveal hypoplasia, optic disc drusen, retinoschisis and foveoschisis, retinitis pigmentosa, chorioretinal folds, or central retinal vein occlusions, or complications from ocular surgery.
An important condition in the differential diagnosis of nanophthalmos is posterior microphthalmos. In posterior microphthalmos, anterior segment parameters are normal or slightly smaller though the axial length is small and the refraction is hyperopic. The posterior segment commonly shows reduction of capillary free zone, crowded optic disc, elevated papillomacular fold, chorioretinal folds, fine retinal folds, uveal effusion syndrome, pigmentary retinopathy and sclerochoroidal thickening on ultrasound.
Correction of the hyperopia with glasses that resemble aphakic spectacles usually results in moderate to good visual acuities. Contact lenses are a better cosmetic alternative. Strabismus surgery can be attempted, but the eyes are usually situated deep in the orbit and difficult to operate. The expansion of the orbital socket can be guided by the axial length of the eye. If the axial length is < 16 mm, the orbital growth is likely to be reduced resulting in facial asymmetries.
Glaucoma is poorly responsive to medications. It can be managed by peripheral iridotomy or peripheral iridoplasty. However, the management of angle closure in nanophthalmos patients is primarily by lens extraction, but complications can occur in up to 40–60% of cases. Intraoperative and post-operative risks include increased rates of corneal endothelial damage, capsular rupture and vitreous loss, intraoperative aqueous misdirection, uveal effusion syndrome, and cystoid macular edema. Prophylactic scleral windows may reduce the rate of complication, owing to a thickened sclera and choroid that may predispose these conditions.
While genetic therapies for nanophthalmos have not yet reached the clinical realm, there is some promise for gene replacement strategies for MFRP based on animal models.
